relation of il23r and il17a gene polymorphisms plus serum levels of il23 and il17a to rheumatoid arthritis susceptibility and activity

Conditions: Rheumatoid Arthritis

Summary: assess the impact of rs2201841 and rs2275913 single nucleotide polymorphism of host genes il-23r and il-17a respectively on susceptibility of rheumatoid arthritis . determine serum levels of il-23 and il-17a using elisa test to investigate their correlation to rheumatoid arthritis disease activity . compare the 4 biomarkers il-23r and il-17a genetic polymorphism and levels of il-23 and il-17a as predictors of rheumatoid arthritis susceptibility and disease activity .

rheumatoid arthritis an autoimmune disease that is associated with progressive disability, systemic complications and socioeconomic costs. ra affects 0.5-1% of the human population making it one of the most common autoimmune disorders. the incidence of ra increases with age, affecting about 6% of the population over 65 years old. women are more affected than men in a ratio of 3:1 (1) . the synovitis in ra is characterized by massive cellular infiltration of the synovium consisting mainly of leukocytes such as t and b cells, macrophages, granulocytes and dendritic cells, together with the increased local production of proinflammatory cytokines and chemokines, eventually leading to the destruction of the joint and bone (2) . th-17 starts producing il-17 and il-22 which in turn stimulate fibroblast-like synoviocytes (fls) to secrete il-8, il-6, ccl20 and cxcl8 causing inflammation, while the macrophages secreted tnf-α results in il-23 production from fls, forming a positive feedback loop that maintains the production of il-17 and il-22 from th-17 (3) . both il-17 and il-22 are able to induce osteoclast differentiation from osteoclast progenitor either directly, or by elevating receptor activator of nuclear factor kappa-b ligand (rankl) on cd4+ and th-17 which upon ligation with the rank receptor on osteoclast progenitor stimulates osteoclast differentiation. osteoclasts are a main cause of bone erosion (4). however, advances in understanding the pathogenesis of the disease have fostered the development of new therapeutics, with improved outcomes (5) . overall, current treatment strategies for ra tend to involve targeting pro-inflammatory cytokines, and thereby the activation process of inflammation, rather than functioning to boost pathways that orchestrate the suppression and resolution of inflammation (6) . il-23 is a pro-inflammatory cytokine that belongs to the il-12 family, together with il-12, il-27, il-35, and il-39 (7) .its actions are mainly mediated by the cd4 t helper subset th17, a distinct subpopulation of gamma/delta t cells (tγδ17 cells), subsets of natural killer t (nkt) cells, and type 3 innate lymphoid cells (ilc3s) (8) the main role of il-23 is to induce the differentiation of αβ t cd4+ naïve cells (th0 cells) in t helper type 17 (th17 cells), (9) which are considered pivotal players in autoimmunity (10) . the il-23 receptor (il-23r) is a heterodimeric receptor composed of 2 subunits: il-12rβ1, in common with the il-12 receptor (il-12r) and il-23rα, specific to il-23 signaling (11). the th17 subset of t-helper cells is pro-inflammatory, plays vital roles in host defense and is involved in the pathogenesis of ra primarily by secreting il-17 (12) . snp is a single base pair mutation at a specific locus, usually consisting of two alleles (where the rare allele frequency is \> 1%). the genetic factors account for 50-60% of all ra cases (13) . some researchers have reported the relationship between il-23r gene polymorphisms and ra risk but got no consistent results . therefore, this study will search the role of il-23r gene rs11209026 polymorphisms in individual susceptibility to ra . many different genetic variants with functional gene polymorphisms may play a culprit role in the underlying pathogenetic mechanisms (14) . il-23r gene variants increase susceptibilities to autoimmune disease in patients with psoriasis, inflammatory bowel disease, and multiple sclerosis (15) . il-17a is a promising target for anti-cytokine therapy in autoimmune arthritis (16). in recent years, the associations between il-17a polymorphisms and ra risk have been studied in various populations by many researchers, (17) with the most frequent variant being il-17a rs2275913 . the il-17a rs2275913 polymorphism is located in the promoter region of the il-17a gene, and cells with the 197a positive allele (genotypes ga/aa) secreted more il-17a than cells with the 197a negative allele (18) . hence, the il-17a rs2275913 polymorphism results in more efficient secretion of il-17a, which may be a potential mechanism by which this polymorphism can increase the risk of developing ra. many studies hypothesized that rs2201841 and rs2275913 snp of il-23r and il-17a genes respectively have good prediction role for ra susceptibility and severity . genetic and experimental data support the concept that the activation of il-23/il-17 axis contributes to the development of a series of inflammatory rheumatic diseases, including, rheumatoid arthritis (ra). it rapidly became a critical target of research to determine predictors of severity to guide therapeutic intervention .

Eligibility criteria:
inclusion criteria: * a total of 45 patients fulfilling the 2010 classification criteria of the american college of rheumatology/european league against rheumatism (acr / eular) will be included in the study. the patients will be recruited from department of physical medicine, rheumatology \& rehabilitation, assiut university hospital. exclusion criteria: * patients with other connective tissue diseases (e.g. sle, systemic sclerosis (ss), bd,...etc), associated autoimmune diseases, chronic liver or kidney diseases, or genetic diseases will be excluded from the study.